Genetic Variant NM_020315.5:c.248A>C (chr22-37659030-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020315.5(PDXP):c.248A>C(p.Glu83Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000255 in 1,176,244 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000019 ( 0 hom. )

Consequence

PDXP
NM_020315.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.97

Publications

0 publications found

Variant links:

Genes affected

PDXP (HGNC:30259): (pyridoxal phosphatase) Pyridoxal 5-prime-phosphate (PLP) is the active form of vitamin B6 that acts as a coenzyme in maintaining biochemical homeostasis. The preferred degradation route from PLP to 4-pyridoxic acid involves the dephosphorylation of PLP by PDXP (Jang et al., 2003 [PubMed 14522954]).[supplied by OMIM, Mar 2008]

PDXP links:

ENSG00000285304 (HGNC:):

ENSG00000285304 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDXP	NM_020315.5 link	c.248A>C	p.Glu83Ala	missense_variant	Exon 1 of 2	ENST00000215904.7	NP_064711.1	Q96GD0-1A0A024R1I3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDXP	ENST00000215904.7 link	c.248A>C	p.Glu83Ala	missense_variant	Exon 1 of 2	1	NM_020315.5	ENSP00000215904.6		Q96GD0-1
ENSG00000285304	ENST00000451997.6 link	c.1501+5157A>C		intron_variant	Intron 16 of 16	2		ENSP00000401076.2		F8WEQ3

Frequencies

GnomAD3 genomes

AF:

0.00000676

AC:

AN:

147952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000194

AC:

AN:

1028292

Hom.:

Cov.:

AF XY:

0.00000204

AC XY:

AN XY:

489264

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20300

American (AMR)

AF:

0.00

AC:

AN:

7578

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11644

East Asian (EAS)

AF:

0.00

AC:

AN:

19818

South Asian (SAS)

AF:

0.0000784

AC:

AN:

25524

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2592

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

883476

Other (OTH)

AF:

0.00

AC:

AN:

38798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000676

AC:

AN:

147952

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

72062

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40888

American (AMR)

AF:

0.00

AC:

AN:

14910

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3416

East Asian (EAS)

AF:

0.00

AC:

AN:

5122

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000151

AC:

AN:

66444

Other (OTH)

AF:

0.00

AC:

AN:

2040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.248A>C (p.E83A) alteration is located in exon 1 (coding exon 1) of the PDXP gene. This alteration results from a A to C substitution at nucleotide position 248, causing the glutamic acid (E) at amino acid position 83 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.047

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.63

M_CAP

Pathogenic

0.71

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

5.0

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.17

Sift

Benign

0.10

Sift4G

Uncertain

0.038

Polyphen

0.45

Vest4

0.32

MutPred

0.55

Gain of MoRF binding (P = 0.0228);

MVP

0.56

MPC

2.7

ClinPred

0.75

GERP RS

3.9

PromoterAI

0.012

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.26

gMVP

0.63

Mutation Taster

=12/88

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_020315.5:c.248A>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over